Poster Presentation GENEMAPPERS 2026

ClinGen Glaucoma Variant Curation Expert Panel guidelines continue to improve classification of MYOC variants (#67)

Patricia Graham 1 2 , Johanna Hadler 2 , Stuart W Tompson 3 , Francesca Pasutto 4 , Kristina Whisenhunt 3 , Owen Siggs 5 , Subhabrata Chakrabarti 6 , Terri L Young 3 , David A Mackey 7 , Kathryn P Burdon 1 , Andrew Dubowsky 8 , Emmanuelle Souzeau 2
  1. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  2. Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia
  3. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
  4. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  5. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  6. Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad, India
  7. Centre for Ophthalmology and Vision Sciences, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Aus
  8. SA Pathology, Adelaide, South Australia, Australia

Pathogenic variants in myocilin (MYOC) are the most common cause of juvenile and adult-onset primary open-angle glaucoma. The Clinical Genome Resource (ClinGen) Glaucoma Variant Curation Expert Panel (VCEP) have published, and recently updated, rule specifications for MYOC variant classification. Here we present the results of the initial curation of MYOC variants and the recent re-curation, using the updated specifications. Version 1 of the VCEP’s specifications were used to curate 265 glaucoma-associated MYOC variants. 30 were classified as pathogenic or likely pathogenic (P, LP), 44 as benign or likely benign (B, LB) and 191 as variants of uncertain significance (VUS). Of the 72 variants already in the ClinVar database, the VCEP’s classifications led to the reclassification of 25 variants, including 8 variants from P/LP to VUS and 11 from VUS to B/LB. Of the 6 variants with conflicting classifications prior to VCEP review, 5 were classified as B/LB and 1 as a VUS. Version 2 of the MYOC specifications were recently used to re-curate the original 265 variants plus 6 newly identified glaucoma-associated variants. An update to REVEL thresholds for the PP3/BP4 criteria in the new specifications, in combination with the inclusion of additional functional assays (PS3/BS3 criteria), were the predominant drivers leading to the reclassification of 43 variants. Importantly, 32 variants have been reclassified out of the VUS group; 19 to P/LP and 14 to B/LB. Although version 2 of the MYOC specifications have improved the classification of variants, there are still 166 variants classified as VUS. Over 90% of these variants have no evidence from functional studies. Appropriate functional assays have the potential to reclassify over half of the VUS as LP or LB, which is important in a clinical setting.